An animal model of painful peripheral neuropathy is produced in the rat by a chronic constriction injury to the sciatic nerve. Animals with this nerve injury have behavioral symptoms that indicate disordered pain sensations like those seen in human syndromes. In particular, the rats have hyperalgesia to thermal and mechanical stimuli, allodynia (pain from normally innocuous stimuli) to touch and cold, and spontaneous pain (or dysesthesias). Immunocytochemical analyses show that the damaged sciatic nerve's primary afferent neurons begin to synthesize neuropeptide Y (NPY) after several kinds of nerve injury (complete transection, the chronic constriction injury, and crush) but not after a painful inflammation of the hind paw. Cell body size and an analysis of the laminar pattern of the nerve injury-evoked NPY increase indicate that the response is largely or entirely within a particular functional class of neurons, the low- threshold mechanoreceptors with large somata and A-beta axons. The nerve injury is known to cause transsynaptic degeneration in small, presumably inhibitory, interneurons in laminae I-III, and this is believed to be due to a NMDA receptor-mediated excitotoxic effect of spontaneous discharge from the damaged primary afferent axons and cell bodies. Such damage would create a state of spinal disinhibition, and electrophysiological evidence for such a state has been found. Dextrorphan, a noncompetitive antagonist of NMDA receptors, reduces the neuropathic hyperalgesia in a dose-dependent way. Further investigation of the transsynaptic degeneration effect has shown that similar, but probably temporary, neuronal damage is caused by a surgical exploration that does not damage the nerve. This indicates that not only abnormal neuropathic pain, but also the ordinary pain of tissue injury can produce excitotoxic damage in the spinal cord. In the case of surgery, this damage is likely to contribute to postoperative pain, and this suggests a role for NMDA antagonists in the control of typical pain states.